INTRODUCTION: Neonates and infants with Down's syndrome (DS)
infrequently develop a condition known as transient abnormal
myelopoiesis (TAM). It has been referred to in literature by varied
nomenclature such as transient leukemia (TL) or transient
myeloproliferative disorder (TMPD).The majority of infants with TAM are
asymptomatic, being picked up incidentally on routine hematologic
testing. Most cases of TAM are known to resolve over the first few
months of life, a small percentage may go on to develop AML within the
first few years of life.

CASE REPORT: We present here a male neonate born to a 36 year-old
mother (G2 P1 L1) by full term normal vaginal delivery; who had a
supervised pregnancy with regular antenatal care. The anomaly scan was
normal. The baby did not cry at birth. The neonate weighed 3 kg at birth
and had bradycardia (heart rate <60/min). The Apgar score was not
known .The respiratory efforts were poor and cyanosis was recorded at
birth. On further examination, the baby had mild dysmorphic features
with a palpable liver (4cm beneath the right costal margin). The child
had generalized edema and poor CNS reflexes.

The child was placed on High Frequency Oscillatory mechanical
ventilation with inotropic support.

The peripheral smear confirmed the above findings, additionally
showing spherocytosis, anisopoikilocytosis and 77nRBCs/100WBCs. The
differential count showed marked left shift up to blasts. Myeloblasts
accounted for 55% of the leucocytes, showing moderate to large sized
cells with high N/C ratio, dispersed chromatin; few showing a single
inconspicuous nucleolus(Fig 2)

In the light of above morphological features and the available
clinical data, a provisional diagnosis of transient abnormal
myelopoiesis (TAM) was given on the peripheral smear. A request was made
to send the peripheral venous blood sample to flow cytometry for
immunophenotyping of the blasts. We also advised a bone marrow study if
it was clinically indicated.

The neonatal asphyxia was compounded by a severe metabolic acidosis
and elevated liver enzymes; and the child succumbed to pulmonary
hemorrhage within few hours of birth, on day one, despite adequate
resuscitative measures.

DISCUSSION: Transient abnormal myelopoiesis (TAM) is the clonal
proliferation of myeloid blast cells which affects an estimated 5-10% of
newborns with Down'ssyndrome. (1) It is also uncommonly described
in phenotypically normal neonates with trisomy 21 mosaicism. (2) The
majority cases of TAM are asymptomatic at presentation and picked up
incidentally on routine hematological testing. Most cases of TAM resolve
with spontaneous remission over the first few months of life, but
13-33%may go on to develop AML within the first four years of life. (3)

Only a handful of cases presenting within few hours of birth have
been described. The typical clinical picture of a patient requiring
treatment is one of an unwell neonate or an infant on intensive care
with an oxygen or inotrope requirement or serious bleed. (3) These
clinical features were consistent with our case. Systemic examination
findings may include hepatomegaly or even hepatosplenomegaly. 2,3.
Rarely clinical complications include cardiopulmonary failure,
hyperviscosity, splenic necrosis and progressive hepatic fibrosis. (4)
The present case concurred partially with these complications; showing
cardiac and respiratory adversities.

Neonates with Down's syndrome are unique in having a
predisposition to transient abnormal myelopoiesis. One of the reasons
hypothesized is that trisomy 21 affects fetal liver hematopoiesis
causing an increase in the megakaryocyte- erythroid progenitor frequency
with common myeloid progenitors and a reduction in the
granulocyte-monocyte progenitors. (5) Increased clonogenicity affecting
megakaryocyte-erythroid progenitors, increased granulocytemonocytes and
colony-forming unit-granulocytes has also been found. (6)

GATA-1 mutations, a transcription factor mutation integral to the
normal development of erythroid, megakaryocytic and basophilic cell
lines, have been associated with TAM and AML in Down's syndrome, as
elucidated by studies done by Tunstall- Pedoe and colleagues. (7) As
such, TAM and myeloid leukaemia of Down's syndrome provides an
excellent model for leukaemogenesis. (8)

TAM is seen as an increase in the number of blasts on peripheral
blood film. Thrombocytopenia is the most common presentation; with
anemia being less frequently encountered. (2) This hematological finding
was noted in our case as well. There may be marked leucocytosis with
fewer blasts in the marrow than peripheral blood. (2,3)

The peripheral blood and bone marrow blasts in TAM have basophilic
cytoplasm with cytoplasmic blebbing, suggestive of megakaryoblasts.2
Blasts in TAM display a characteristic immunophenotype.9 In most cases
the blasts are positive for CD34, CD56, CD117, CD13, CD33, CD7, CD4
(dim), CD4, CD42, TPO-R, CD36, CD61 and CD71.The blasts are negative for
MPO, CD15, CD14 and glycophorin A. Antibodies to CD41 and CD61 are
considered useful in identifying cells with megakaryocytic lineage in
immunologic preparations. (2) Due to the early death of the neonate in
our case, flow cytometry could not be performed.

Factors associated with early death in TAM include a high white
cell count, increased liver enzymes, failure to normalize the blood
count, ascites, preterm delivery, bleeding diatheses and failure of
spontaneous remission. (1) Three of these variables were seen in our
case as well, probably accounting for the early neonatal death.
Interestingly, TAM can occur in-utero and be a cause of foetal death.
(3)

Morphologically distinguishing TAM from congenital acute leukaemia
is a diagnostic challenge for a hematopathologist; especially in smaller
centers where ancillary studies may not be available. The difference in
survival rates (being in favour of TAM) also merits a morphological
differentiation. Also, with the incidence of overt acute leukaemia being
markedly increased in infants with Down's syndrome, the distinction
between TAM and acute leukaemia is imperative. The characteristics
common to both TAM and congenital acute leukaemias include a clonal
nature, as demonstrated by molecular studies and an association with
Down's syndrome. Trisomy 21 is the recurrent chromosomal anomaly in
both conditions. However, TAM may have cryptic inversions of chromosome
21 as opposed to interstitial deletions of 21q in acute leukaemias.
(10,11,12) The differentiating features particular to acute leukaemia
include "presentations after 6 months of age and variable WBC
counts with striking dyspoiesis. The circulating blasts in acute
leukaemia are more phenotypically uniform; as opposed to a more
heterogeneous blast population in TAM. (13,14,15) The bone marrow study
usually reveals a diffuse replacement of the marrow by blasts in acute
leukaemia whereas TAM may have a lower percentage of blasts than in
peripheral blood. The spectrum of blasts in TAM ranges from myeloid
(typically lacking Auer rods), megakaryoblasts (being more abundant) and
erythroblasts. Acute leukaemia on the other hand comprises of
megakaryoblastic (in children <3 years) or lymphoblastic in older
children (>3 years). While TAM has a good prognosis, dictated by a
spontaneous resolution in 2-3 months; acute leukaemia portends a poor
prognosis, mandating an aggressive chemotherapy.

CONCLUSION: Transient abnormal myelopoiesis (TAM) is a condition
with clonal proliferation of myeloid blast cells in newborns with
Down's syndrome. Recognizing this entity is of clinical and
academic importance since it carries a better prognosis compared to its
more sinister counterpart, congenital leukaemia.